This study presents the first investigation of the antiviral effects of the liposome-encapsulated PolyICLC (LE-PoIylCLC) on Dengue virus (DENV) in a mouse model. In vivo efficacy studies showed that LE-PolylCLC acted to increase antiviral mechanisms mainly through promoting cytokine expression associated with innate immunity, such as IFN-gamma. In addition, the pro-inflammatory cytokine TNF-alpha was also increased, while IL-6 level was decreased in serum. The titers of total antibodies against DENV2 in mice were also elevated. Administration of LE-PolyICLC not only alleviated the loss of body weight, degree of morbidity, and pathological damage in brains, but also reduced the viral titers and expression of viral E protein in the brain. Notably, the effectiveness of LE-PolyICLC was better than PoIylCLC on the basis of the data presented in this study. These results, therefore, set a foundation for further development of LE-PolyICLC as an attractive candidate of antiviral agents to be used in both prophylactic and therapeutic settings in DENV diseases. (C) 2016 Elsevier Inc. All rights reserved.